Epidemiology and Social: Editorial Comment
In Cambodia, where 78% of people earn less than US$ 2 dollars per day, UNAIDS estimates that 130 000 people are currently infected with HIV; 16 000 Cambodians have already died with HIV infection . Providing optimal treatment and care for large numbers of HIV-infected people is clearly a challenge in countries with limited resources. In this issue of AIDS, Madec and colleagues examined responses to HAART among 1735 severely immuno-compromised patients, who joined a Médecins Sans Frontières-sponsored treatment access programme in Phnom Penh . The median CD4 cell count at initiation of HAART was 20 cells/μl, with 75% of patients starting with fewer than 78 cells/μl. Those with CD4 cell counts below 20 cells/μl at initiation of HAART had a 2-year mortality rate of 24.7%, versus 2-year rates of 4–7% for those with higher baseline CD4 cell counts. Those with missing CD4 cell counts at baseline (i.e. those with very poor health status who did not need CD4 cell counts to decide on HAART initiation) had the highest mortality.
International treatment guidelines recommend initiation of HAART while the CD4 cell count is still above 200 cells/μl if funding is available [3,4], since later initiation of HAART has been associated with higher mortality [5,6]. However, the issue of late treatment initiation is a problem in both developing and developed countries. The median CD4 cell count at initiation of HAART was between 80 and 100 cells/μl for other large access programmes in sub-Saharan Africa [7–9]. In recent North American and European cohort studies, around 50% of patients have initiated HAART with CD4 cell counts below 200 cells/μl [10,11]. As the authors conclude, the relatively poor survival for the lowest CD4 cell count group treated in Cambodia is another reminder of the need for earlier diagnosis of HIV infection.
The antiretrovirals used in the Cambodian programme included stavudine/lamivudine with either nevirapine or efavirenz. The large majority of patients in access programmes in sub-Saharan Africa and Asia have also used the fixed dose combination of stavudine, lamivudine and nevirapine,  showing strong antiviral efficacy  and dramatic reductions in AIDS-related mortality . However this combination no longer has the highest recommendation as first-line treatment in guidelines documents, which now favour the use of tenofovir, abacavir or zidovudine over stavudine, and efavirenz over nevirapine [3,4]. The Gilead 903 study showed equivalent antiviral efficacy for stavudine/lamivudine/efavirenz and tenofovir/lamivudine/efavirenz over 3 years, but with higher rates of lipodystrophy for the stavudine versus the tenofovir-treated group (19 versus 3%) . The 2NN trial compared stavudine/lamivudine/nevirapine and stavudine/lamivudine/efavirenz, and did not show equivalent efficacy for the two arms; however the difference in efficacy, favouring efavirenz, was small and not statistically significant . In the Cambodian cohort, there was no difference in survival between those treated with efavirenz versus nevirapine; however this was not a randomized comparison. Even so, first-line treatment in North America and Europe has already moved away from the use of stavudine and nevirapine, although these drugs are still widely used in Africa and Asia.
The dilemma for countries such as Cambodia, with fixed and limited healthcare resources to treat large epidemics, is whether to treat more patients with the cheapest HAART regimens, or whether to use more expensive combinations which might prevent others from accessing HAART at all. Table 1 shows minimum prices for first-line nucleoside reverse transcriptase inhibitor (NRTI)/non-nucleoside reverse transcriptase inhibitor (NNRTI) combinations, using the recently published Medicins san Frontieres 2006 drug prices for least developed countries . Assuming that, in addition to antiretroviral costs, the cost of patient care is US$ 300 per person-year, in line with a recent Cambodian survey , the number of people who can be treated for a fixed US$ 1 million budget is shown in the right-hand column. For a fixed budget for treatment and care of HIV-infected people in a country like Cambodia, it would be possible to treat double the number of patients with stavudine/lamivudine/nevirapine, relative to tenofovir/emtricitabine/efavirenz. If budgets are limited, use of the more expensive combinations may slightly improve efficacy, and lower rates of adverse events for the 50% of patients accessing these treatments, but could also prevent the other 50% of patients from accessing HAART at all.
Given that there is still a large shortfall in the number of HIV-infected people receiving treatment in developing countries, there are three potential outcomes to this apparent dilemma. First, treatment budgets for the Global AIDS Fund and similar programmes could be increased to account for higher costs of new combinations; second patients would be kept on stavudine/lamivudine/nevirapine until development of treatment-limiting toxicity and then switched to more expensive antiretrovirals; or third, more research on manufacturing and dose-optimization may lead to further reductions in the costs of the most modern NRTI/NNRTI combinations.
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